Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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2,3-Dimethoxy-5-methyl-p-benzoquinone (Coenzyme Q0) Disrupts Carbohydrate Metabolism of HeLa Cells by Adduct Formation with Intracellular Free Sulfhydryl-Groups, and Induces ATP Depletion and Necrosis
Takayuki TakahashiYukitoshi MineTadashi Okamoto
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2018 Volume 41 Issue 12 Pages 1809-1817


2,3-Dimethoxy-5-methyl-p-benzoquinone is a common chemical structure of coenzyme Q (CoQ) that conjugates different lengths of an isoprenoid side chain at the 6-position of the p-benzoquinone ring. In a series of studies to explore the cytotoxic mechanism of CoQ homologues with a short isoprenoid side chain, we found that a CoQ analogue without an isoprenoid side chain, CoQ0, showed marked toxicity against HeLa cells in comparison with cytotoxic homologues. Therefore, we examined the cytotoxic mechanism of CoQ0. Different from the cytotoxic CoQ homologues that induced apoptosis, 100 µM CoQ0 induced necrosis of HeLa cells. The CoQ0-induced cell death was accompanied by a decrease in endogenous non-protein and protein-associated sulfhydryl (SH)-groups, but this improved with the concomitant addition of compounds with SH-groups but not antioxidants without SH-groups. In addition, UV-spectrum analysis suggested that CoQ0 could rapidly form S-conjugated adducts with compounds with SH-groups by Michael addition. On the other hand, enzyme activities of both glyceraldehyde-3-phosphate dehydrogenase, which has a Cys residue in the active site, and α-ketoglutarate dehydrogenase complex, which requires cofactors with SH-groups, CoA and protein-bound α-lipoic acid, and CoA and ATP contents in the cells were significantly decreased by the addition of CoQ0 but not CoQ1. Furthermore, the decrease of an endogenous antioxidant, glutathione (GSH), by CoQ0 treatment was much greater than the predicted increase of endogenous GSH disulfide. These results suggest that CoQ0 rapidly forms S-conjugate adducts with these endogenous non-protein and protein-associated SH-groups of HeLa cells, which disrupts carbohydrate metabolism followed by intracellular ATP depletion and necrotic cell death.

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